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Publication numberUS3234090 A
Publication typeGrant
Publication dateFeb 8, 1966
Filing dateSep 10, 1962
Priority dateSep 10, 1962
Publication numberUS 3234090 A, US 3234090A, US-A-3234090, US3234090 A, US3234090A
InventorsHuebner Charles Ferdinand, Bencze William Laszlo
Original AssigneeCiba Geigy Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Pharmaceutical compositions comprising saturated basic ethers
US 3234090 A
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Description  (OCR text may contain errors)

United States Patent 3,234,090 PHARMACEUTICAL COMPOSITIONS CDMPRISING SATURATED BASIC ETHERS Charles Ferdinand Huebner, Chatham, and William Laszlo Bencze, New Providence, N.J., assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 10, 1962, Ser. No. 222,627 3 Claims. (Cl. 167-58) This is a continuation-in-part application of our application Serial No. 160,291, filed December 18, 1961, now abandoned.

The present invention concerns basic others. More particularly, it relates to compounds having the formula in which Ph is a 1,2-phenylene radical, Ar is a monocyclic carbocyclic aryl group substituted by tertiary aminolower valkyl-oxy, in which tertiary amino is separated from oxy by at least two carbon atoms, R is hydrogen, an aliphatic radical, a carbocyclic aryl radical, a carbocyclic aryl-aliphatic radical, a heterocyclic aryl radical or a heterocyclic aryl aliphatic radical, the group of the formula -(C,,H stands for an unbranched alkylene radical having from three to five carbon atoms and carrying the groups Ar and R, salts, N-oxides, salts of N-oxides or quaternary ammonium compounds thereof, as well as procedure for the preparation of such compounds.

The 1,2-phenylene (o-phenylene) radical is unsubstituted or may be substituted by one or more than one of the same or of different substituents attached to any of the four positions available for substitution. Substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isotpropyl and the like, hydroxyl, etherified hydroxyl, such as lower alkoxy, e.g. methoxy, ethoxy, npr-opyloxy, isopropyloxy, n-butyloxy and the like, lower alkenyloxy, e.g. allyloxy and the like, lower alkylene dioxy, e.g. methylenedioxy and the like, esterified hydroxyl, such as halogeno (representing hydroxyl esterified by a hydrohalic acid), e.g. fluoro, chloro, bromo and the like, nitro, amino, such as N,Ndi-1ower alkylamino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, trifiuoromethyl, acyl, such as lower alkanoyl, e.g. acetyl, propionyl, pivaloyl and the like, benzoyl, pyridoyl, e.g. nicotinoyl and the like, or any other suitable substituent. The 1,2-phenylene group Pb in the above formula is primarily 1,2-phenylene, (lower alkyl)- 1,2-phenylene, (hydroxy)-1,2-phenylene (e-therified 11ydroxy)-1,2-phenylene, such as lower alkoxy)-1, 2-phenylene, (lower alkenyloxy)-l,2 phenylene, (lower alkylenedioxy)-1,2-phenylene and the like, (esterified hydroxy)- 1,2-pheuylene, such as (halogeno)-1,2-phenylene and the like, (nitro)-1,2-phenylene, (amino)-1,2-phenylene, such as (N,N-di-lower a1kyl-arnino)-1,2-phenylene and the like, (trifiuoromethyl)1,2-phenylene, (acyl)-l,2-phenylene, such as (lower alkanoyl)-l,2-phenylene, (benzoyl)- 1,2-phenylene, (pyridoyl)-1,2-phenylene and the like, or any other suitably substituted- 1,2-phenylene group.

The group of formula -(C,,H represents an unbranched alkylene radical having from three to five carbon atoms (the letter is in the above groups stands for an integer from three to five); this alkylene radical is attached to the two adjacent positions of the 1,2-phenylene radical Ph and carries the groups Ar and R defined below. Thus, an unbranched alkylene radical of the formula --(C H represents 1,3-propylene, 1,4-

ice.

butylene or 1,5-pentylene, to which are attached the groups Ar and R. The compounds of this invention are, therefore, compounds of the indane series, as well as compounds having the 1,2,3,4-tetrahydronaphthalene, benzosuberane and the like, ring systems.

A tertiary amino-lower alkyl-oxy substituent, which may be attached to any of the positions, preferably to the 4-position, available for substitution in the monocyclic carbocyclic aryl group Ar, may be represented by the formula: -O-(C H )Am, in which the group of the formula (C H standsfor lower alkylene, having preferably from two to seven carbon atoms (i.e. the letter In is an integer having preferably from two to seven, both inclusive), and separates the tertiary amino group Am from the oxygen atom by at least two carbon atoms. The group of the formula --(C,, =H stands preferably for alkylene having from two to three carbon atoms (i.e. the letter m stands preferably for an integer from two to three) and separates the tertiary amino group Am from the oxygen atom by two to three carbon atoms. Such alkylene group is preferably 1,2-ethylene, 1-methyl-1,2-ethylene, 2-methyl-1,2-ethylene, 1,3-propylene, but may also be 1,3-butylene, 2,3-butylene, 3,4-butyl-v ene, 1,4-buty-lene, 1,4-pentylene, 1,5-pentylene, 1,5-hexylene, 1,6-hexylene, 1,7-heptylene and the like.

A tertiary amino group, such as the group Am in the above formula, is, for example, N ,N-di-su-bstituted amino, in which each of the substituents is, for example, an aliphatic radical, such :as lower alkyl, lower alkenyl, and the like, a cycloaliphatic radical, such as cycloalkyl and the like, a cycloaliphatic-aliphatic radical, such as cycloalkyl-lower alkyl and the like, a carbocyclic aryl radical, such as monocyclic carbocyclic aryl and the like, a carbocyclic aryl-aliphatic radical, such as monocyclic canbocyclic aryl-lower alkyl and the like, which radicals have from one to ten carbon atoms. Preferred as substituents are lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl, neopentyl and the like; other substituents are lower alkenyl, e.g. allyl, Z-methylallyl and the like, cycloalkyl having from three to seven, preferaby from five to six, ring carbon atoms, e.g. cyclopentyl, cyclohexyl and the like, cycloalkyl-lower alkyl, in which cycloalkyl has from three to seven, preferably from five to six, ring carbon atoms, e.g. cyclopentylmethyl, 2-cyclohenxylethyl and the like, monocyclic carbocyclic aryl, e.g. phenyl and the like, or monocyclic carbocyclic aryl-lower alkyl, such as phenyllower alkyl, e.g. benzyl, l-phenylethyl, Z-phenylethyl and the like. N,N-di-substituted amino groups are primarily N,N-di-lower alkyl-amino, in which lower alkyl has preferably from one to four carbon atoms, e.g. N,N dimethylamino, N-methyl-N-ethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N,-di-isopropylamino and the like, as well as l -cycloalkyl-N-lower alkyl-amino, in which cycloalkyl has from five to six ring carbon atoms, and ower alkyl has preferably from one to four carbon atoms, e.g. l -cyclopentyl-N-methyl-amino, N-cyclohexyl- N-methyl-amino, N-cyclohexyl-N-ethyl-amino and the like, or N-lower alkyl-N-phenyl-lower alkyl-amino, in which lower alkyl has preferaby from one to four carbon atoms, e.g. N-benzyl-N-methyl-amino, N-benzyl-N- ethyl-amino, N ethyl N-(1-phenylethyl)-amino, N methyl-N-(Z-phenylethyD-amino and the like, or any other equivalent NJl-di-substituted amino group. The substitucnts, particularly lower alkyl, may also carry functional groups, such as hydroxyl, lower alkoxy, e.g. methoxy, ethoxy and the like, lower 'alkyl-rnercapto, e.g. methylmercapto, ethylmercapto and the like, or any other suitable functional group. N,N-di-substit uted-amino groups, in which the substituents carry functional groups, are, for example, N-hydroxy-lower alkyl-N-lower -alk yl amino, e.g. N-(Z-hydroxyethyl)-N-methyl-amino and "the H V a 3 1 like, N,N-di-hydroxylower alkyl-amino, e.g. N,N-di-(2- hydroxyethyl)-amino and the like.

The tertiary amino group, such as the group Am in the above formula, may also represent 1-N,N-alkylene-imino,

in which alkylene has from four to eight carbon atoms,

1-N,N-aza-alkylene-imino group, in which alkylene has from four to six'carbon atoms, or 1-N,N-oXa-'alkyleneimino and 1-N,N-thia-alkylene-imino, in which:al'kylenehas preferably four carbon atoms. Together'with the nitrogen atom, these alkylene, aza-alkylene oxa-alkylene or thia-alkylene radicals represent l-N,N-alkylene-imino,

in which alkylene has from four to eight carbon atoms, such as l-pyrrolidino groups, e.g. 1-pyrrolidino,'2-'methyll-pyrrolidino and the like, l-piperidin-o groups, e.g. 1-

piperidino, Z-methyl-l-piperidino, 4-methyl-l piperidino,

3-hydroXy-1-piperidino, 3-acetoXy-1-piperidino, 3-hydroxymethyl-l-piperidino and the like, 1-N,N-(1,6-hexylene)- imino, 1-N,N-(1,7-heptylene)-imino and the like, l-N,N- (azo-alkylene)-imino, particularly l-N',N-(N-loweralkylaza-alkylene)-imino, in 'which'alkylene has from four to six carbon atoms, such as l-piperazino or particularly 4-lower alkyl-l-piperazino, e.g. 4-methyl l piperazino, 4-ethyl-l-piperazino and they like, as well as 4-hydroxyethyl-l-piperazino, 4-acetoxyethyl 1 piperazino and the like, '1-N,N'-(3-aza-1,6-hexylene)-imino, particularly 1- N,N-(3-aza-3-lower alkyl 1,6 hexylene) imino, e.g. 1-

N,'N-(3-aza-3-methyl-1,6-hexylene)-imino and the like, or

1-N,N-4-aza-1,7-heptylene)-imino, particularly 1N',N- (4-aza-4-lower alkyl-l,7-heptylene)-imino, e.g. 1-N,N-(4- aza-4 methyl-1,7-heptylene)-imino and the like, 4-morpholino groups, e.g. 4-morpholino,-3-methyl-4-morpho lino and the like, 4-thiamorpholinogroups, e.g. 4-thiamorpholino and the like, or any other equivalent tertiary.

amino group.

In the tertiary amino-lowerv alkyl-oxy group, the lower 1 alkyl group, either partially orin toto,'may form part of i a saturated heterocyclic ring system, of which the tertiary amino group Am is a member and is separated from the oxy group by at least two carbon atoms. Such tertiary amino-lower'alkyl group is', for example, l-methyl-Z-piperidinomethyl, 1-methyl-3-piperidinomethyl, '1 ethyl 4- piperidino, 1-methyl-3-pyrro1idinomethyl and the like.

Apart from the tertiary amino-lower alkyl-oxy group the monocyclic carbocyclic aryl group Ar, which repre-, sents above all a .tertiary amino-lower alkyl-oxy-phenyl. group, may have one or more than one other substrtuent,

which may be attached to any of the positions available for substitution. Such substituents are represented above r all by halogeno, e.g. fluoro, chloro, bromo or iodo, as well i as by lower alkyl, e.g. methyl, ethyl, isopropyl and the,

like, lower 'alkoxy, e.g. methoxy, ethoXy, n-propylo'xy and, P

the like, h-alogeno-lower alkyl, e.g. trifluoromethyl and the like, or any other suitable substituent, for example, an i additional tertiary amino-lower alkyl-oxy group of the The group R attached to one of the carbon atoms of 1 the alkylene group of the formula .-(C,,H 1s pr1- I inarily hydrogen, but may also stand for an aliphatic,

group, particularly lower alkyl, eg. methyl, ethyl; n-

propyL-isopropyl and the like, a carbocyclic aryl, particularly a monocyclic carbocyclic aryl, radical, e.g. phenyl I or substituted phenyl, in Whichone or more than one. of a the same or of different sub-stituents may substitute any of the positions available for substitution, such as (lower; f

alkyl-phenyl, in which lower alkyl has preferably from one to four carbon atoms and is, for example, methyl, ethyl,- n-propyl, isopropyl, n-butyl and the like, (lower; alkoxyJ- phenyl, in which lower alkoxy has preferably from one to four carbon atoms, and represents, for example, methoxy,

ethoxy, n-propyloxy, ispropyloxy and the like, (halogeno)- phenyl, in which halogeno stands for fluoro, ch1oro,bromo and the like, (nitro)-phenyl, (N,N-di-lower alkyl-amino)- phenyl, in which lower alkyl has preferably fromone;

to four carbon atoms, and N,N-di-lower alkyl-amino is,

for example, N',N-dimethyl-amino, N ethyl N'- methylamino, N,N.-diethylamiuo and the like, (tri-fluoromethyl)'- phenyl and the like, as Wellas [Am+(C H )O]-;

phenyl, in .which Amand the: group (C I- I )-have .the previously given meaning, a carbocyclic aryl-aliphatic,

such as a monocyclic carbocyclic aryl-lowersalkyl, radical,

particularly phenyl-lower alkyl, e.g.benzyl,i1-phenylethyl, 2-phenylethyl, diphenylmethyl and the; like, or substituted phenyl-lower alkyl,;such as (lower alkyl)- phenyl-lower alkyl, ,(lower, alkoXy)-phenyl-lower alkyl, (halogeuo)- phenyl-lo-wer alkyl, (nitro)-phenyl-lower* alkyl, (N,N-dialkyl and the like, in which lower alkyl, lower alkoxy, halogeno, N,N'-di-lower alkyl-amino, and,

have the previously-given meaning, a ,heterocyclie aryl, particularly monocyclic heterocyclic aryl, radical, such as pyridyl, e.g. 3-pyridyl, 4-pyridyl and the like, or a heterocyclic aryl-aliphatic, particularly a monocyclic heterocyclic aryl-lower alkyl, radical, such as pyridyl -lower alkyl, eg-

2-pyridylmethyl and the: like.

Salts of the compounds of this invention are acid fiddle .1

tion salts, such as pharmaceutically acceptable,.non-toxic acid .additionsalts with inorganic or organic acids, for

example,1mineral acids, e.g. hydrochloric, hydrobromic,

sulfuric, phosphoric acids and the like, organic carboxylic acids, e.g. acetic,. propionic, pivalic, glycolic,x1actic',

malonic', .succinic', maleic, hydroxy-maleic, malic, tartaric, citric, benzoic; salicyclic, ,2-acetoxybenzoic,v ,nicotinic,:

isonicotinic acid and the like, orany other suitable car-,3 boxylic acid, it as well as organic sulfonic acids, e.g.- methane sulfonic, ethanet sulfonic, ethane, l,2-disulfonic,; 2-.hydroxyethane sulfonic, p-toluene sulfonic, naphthalene 2-sulfonic acid and the like, orany other suitable acid.

Other acidadditionssalts'may be useful as intermediates in the preparation of pharmaceutically acceptable, nontoxic acid addition salt-sor in the purification of; thefree. base, aswell as for identification or characterization purposes. Salts, which are prepared primarily ;for identification purposes, are, for example, those with acidic organic,

nitro compounds, e.g. picric, picrolonic, fiavianic acid and the like, or metal complex acid, e.g. phosphotungstic, phosphomolybdic, chloro-platinie, Reinecke acid and the like. Mono or poly-salts may be formed depending on the number of salt-forming groups and/ or the conditions used for the salt formation.-

Also included within the scope of the. present invention arethe :N-oxides: of the aforementionedcompounds, as

well as the acidadclitionsalts of such Ni-oxides, for'eXam alkane sulfonates, e.g. methyl; Z-hydroxy-ethane sul-fonate.

and thelike, ortlower, alkyltmonocyclic carbocyclic'aryl sulfonates; e.g. methyl p-toluene sulfonate, ethyl.,p-toluene:; sulfona-te, and the like, .as well as those .withicarbocyclic;

aryl-aliphatic halides, suchasphenyl-lower alkyl halides, e.g. benzyl, l-phenylethyl: or 2-phenylethyl chloride, bromide or iodide and the like. Also included as'quaternary ammonium1 compounds are the corresponding quaternary ammonium hydroxides,= and the quaternary ammonium salts with other. acids; particularly those with the organic carboxylic' acidsfjmentioned hereinabove.

The compounds of this invention have antifungal prop- .erties and can be :used'a-ccordingly. For example, they show antidernatophyte effects against fungi causing superficial dermatophytoses, such as T richophyton mentagrophytes, and can be used in the treatment of infections caused by such microorganism.

In addition, compounds of this invention have estrogenic properties, and can be used accordingly, for example, in raising animals to obtain increased weight gain and increased efliciency of feed utilization and the like.

Particularly useful are the compounds of the formula:

CH2) n in which Ph' stands primarily for 1,2-phenylene, as well as (lower alkyl)-l,2-phenylene, (lower alkoxy)-l,2-phenylene, (halogeno)-l,2-phenylene, (nitro)-l,2-phenylene, (N, N-di-lower alkyl-amino)-l,2-phenylene or (trifluoromethyl)-1,2-phenylene, the group of the formula stands for an unbranched alkylene radical having from two to three, preferably two, carbon atoms (i.e. the letter n stands for one of the integers 2 and 3, preferably for the integer 2), Am stands above all for N,N-di-lower alkyl-amino, as well as N,N-alkylene-imino, in which alkylene has from four to seven carbon atoms, 4-morpholino or 4-1ower alkyl-l-piperazine, the group of the formula -'(C 'H stands for alkylene having from two to three, preferably two, carbon atoms (i.e. the letter m stands for one of the integers 2 and 3, preferably for the integer 2), and separates the group Am from the oxygen atom by two to three, preferably by two, carbon atoms, Hal stands for halogeno, especially chloro, as well as bromo and the like, and the letter p stands for one of the integers 0, 1 and 2, particularly for 1, and acid addition, particularly pharmaceutically acceptable, non-toxic acid addition salts thereof.

The compounds of the present invention may be prepared according to methods known per se, for example, by converting in a compound having the formula:

in which Ph, R, and the group of the formula have the previously given meaning, and Ar is a monocyclic carbocyclic aryl radical substituted by a hydroxyl group, or preferably a metal compound thereof, the hydroxyl group of the radical Ar into a tertiary amino-lower alkyl-oxy group, and, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting compound into an N- oxide or a quaternary ammonium compound there, and/ or, if desired, converting a resulting compound or an N-oxide into a salt thereof, and/or, if desired, converting a quaternary ammonium compound into another quaternary ammonium compound, and/or, if desired, separating a mixture of isomers into the single isomers.

The conversion of the hydroxyl group attached to the radical Ar into the desired tertiary amino-lower alkyloxy group is carried out according to known procedures. For example, the starting material having the phenolic hydroxyl group attached to the group Ar may be converted into a metal salt, particularly an alkali metal, e.g. lithium, sodium, potassium and the like, salt. Formation of the metal compound may be achieved, for example, by reacting the starting material with a metal compoundforming reagent, such as an alkali metal hydride 0r amide, e.g. lithium hydride, sodium hydride, sodamide, potassium amide and the like, or any other suitable reagent, such as an alkali metal lower alkanolate, e.g. lithium, sodium or potassium methanolate, ethanolate, tertiary butanolate and the like, or an alkali metal compound of a hydrocarbon, eg. butyl lithium, phenyl lithium, phenyl sodium and the like. The preparation of the metal compounds is carried out in the presence of an inert solvent, e.g. hexane, benzene, toluene, xylene, diethyl ether, p-dioxane, tetrahydrofuran, diethyleneglycol dimethylether, N,N-dimethylformamide and the like, or any other suitable solvent, such as a lower alkanol, e.g. methanol, ethanol and the like.

The starting material, particularly the metal compound thereof, is then reacted with a reactive ester of a tertiary amino-lower alkanol, particularly a compound of the formula Am(C I-I )X, in which Am and the group of the formula (C H have the previously given meaning, and X stands for a reactive esterified hydroxyl group. The latter is above all a hydroxyl group esterified with a strong mineral acid, such as hyd-rohalic acid, e.g. hydrochloric, hydrobromic acid; therefore, the group X represents primarily halogeno, e.g. chloro, bromo and the like. It may also be a hydroxyl group esterified with a strong organic sulfonic acid, such as a lower alkane sulfonic acid, e.g. methane sulfonic, ethane sulfonic acid and the like, or a monocyclic carbocyclic aryl-sulfonic acid, e.g. p-toluene sulfonic acid and the like; thus, the group X may also stand for lower alkyl-sulfonyloxy, e.g. methylsulfonyloxy, ethylsulfonyloxy and the like, or monocyclic carbocyclic aryl-sulfonyloxy, e.g. p-tolylsulfonyloxy and the like. The preferred reactive esters of a tertiary amino-lower alkanol are those having the formula Am(C I-l )Hal, in which Am, and the group of the formula (C,,,H have the previously given meaning, and Hal represents halogeno, particularly chloro.

The reaction of the starting material, particularly a metal compound thereof, with the reactive ester of a tertiary amino-lower alkanol is carried out in a suitable diluent, for example, in the solvent used for the preparation of a metal compound, if necessary, While cooling or at an elevated temperature, and/ or, in the atmosphere of an inert gas, e.g. nitrogen.

The starting material used in the above reaction is known or may be prepared according to known methods.

The compounds of this invention may also be prepared, for example, by reacting a compound having the formula:

1 11 (birth-2 in which Ph, Rand the group of the formula have the previously given meaning, and Ar" is a monocyclic carbocyclic aryl radical substituted by a reactive esterified hydroxy-lower alkyl-oxy group, in which the re active esterified hydroxy portion is separated from oxy by at least two carbon atoms, with a secondary amine, and, if desired, carrying out the optional steps.

A reactive esterified hydroxy-lower alkyl-oxy group is particularly a group of the formula O-(C H )-X, in which X and the group of the formula --(C,,,H have the previously given meaning; the reactive esterified group X is primarily a group Hal representing halogeno, particularly chloro, as well as a suitable organic sulfonyloxy group. The reaction of the starting material with the secondary amine, having preferably the formula H+Ani,

in which ,Am has the above given meaning, is carried out in such manner, that an excess of the amine or of any other suitable base is present to neutralize the generated acid; if necessary, the reaction mixture may be diluted with, a suitable inert solvent. 7

The starting material used in the above reaction is prepared according to known methods, for example, by reacting the alkali metal compound of the starting material of the previous procedure with a halogeno-lower alkanol, and converting in a resultingicompound, in which the monocyclic carbocyclic aryl group has a hydroxy-lower alkyloxy substituent, the hydroxyl group of such substituent into an esterified hydroxyl group, for example,'by

treatment with a thionyl halide, eg. thionyl chloride and the like, or with an organic sulfonic acid halide, e.g. chloride and the like, in the presence of a suitable base, e.g. pyridine and the like.

The compounds ofthis invention may also be prepared by converting in a compound of the formula which Ph, Ar and R have the previously given meaning, and the group of the formula -(C H is an unbranched alkenylene radical having from three to five carbon atoms and carrying the groups Ar and R, thealkenylene' radical of the formula (C H into the desired alkylene radical ofthe formula having from three to five carbon atoms and carrying the groupsAr and R, and, if desired, carryingout the optional steps.

The conversion of the alkenylene radical into an alkylene radical is carried out according to methods known per se, for example, by treatment with an alkali metal, eg sodium and the like, in the presence of a lower alkanol, with metal amalgam in the presence of a hydrogen donor, e.g. sodium amalgam in the presence of moist diethyl ether, catalytically activated hydrogen, such as bydrogen in the presence of a palladium catalyst and the like, or any other suitable method.

The starting materials used in the above reaction may be prepared, for example, by converting in a compound of the formula I 11 (bani-i) in which Ph, Ar, R and the group of the formula have the previously given meaning, or preferably a metal salt thereof, the hydroxyl group of the radical Ar into a tertiary amino-lower alkyl-oxy group; this reaction 'is carried out as previously shown, for example, by reacting the metal salt with a reactive ester of a tertiary aminolower' alkanol. ing a group Ar substituted by hydroxyl may be prepared, for example, by reacting a benzocycloalkanone com- The above unsaturatedcompounds hay-- pound, inwhich the cycloalkane, portion carries thesub- The compounds of this invention may also be prepared,

for example, by replacing in-acoinpoundof the formula 1 (cairn-ion) R in which Ph, Anand R have the previously-given meaning, and the radical of the formula ,(C H OH)- is an unbranched alkylene radical having from three to five carbon atoms and carrying, in addition to the groups Ar and R, the hydroxyl group OH, the latter by hydrogen,

and carrying out the optionalsteps.

The hydroxyl group-Ol-Iis preferably attached to the same carbon atom as the, group gAr,-particular1y in case the latter substitutes a carbon atom adjacent to the 1,2-'

phenylene radical. It may be replaced, for example, by

treating the starting material with hydrogen inthepresence of'a catalyst, e.g. a palladium catalyst (for example,

in the presence ofcacetic acid), Raney nickel. and thelike; if necessary, at. an increased pressure and/or at an elej-- vated temperature. a

The starting materials used in the abovereaction-are prepared according to known methods, for example, by reacting a compound .of the formula.

in which Ph andsR have the; previously-given meaning; and the group of the formula-(C,,H =O is an un- 1 branched alkylene radical having from-three to'five carbon atoms and carrying, addition tothe. groupgR, the oxo group ,=O, witha ,Grignard reagent of the: formula HalMg@[Ar] in which Ar :hasthezpreviously-given meaning, and Hal is halogeno, particularly bromo and the i like, andcarefully decomposing the resulting complex, for example, with aqueous ammonium chloride. The intermediates used in the above Grignard reaction are known or may be prepared according to known methods; the Gri-Q guard reagentmay be prepared, forexample, according to the Method of-Entrainment,- described by Kharash and a Reinmuth, Grignard Reactions of Nonmetallic Substances (Prentice-Hall, 1954). abovementionedbrganic radical, the; starting material may'also be prepared, for'exarnple, by reacting a COII1- pound of the formula lfh (cums-3:0

in which Ph, Ar and the group of the formula have the previously-given meaning, with a reagent of the formula HalMg [Ra] in which Hal has thepreviouslygiven means, and R5? standsifor one of the organic radi-r cals-representing the group R.

The starting materials prepared according to the above:

proceduremay also serve as intermediates for the preparation ofthe starting materials used in the previously-described method to form the compounds: ofthis invention;

upon dehydration, for example,-in the presenceof anacid, e.g. hydrochloric, sulfuric acid and the like, they are converted into the compounds'of the formula 1 in which. Ph, Ar, R and the radical of the formula have the previously=given meaning.

In case-of R being one of the- 9 The compounds of this invention may also be prepared, for example, by reacting. a compound of the formula Ifh (cairn-3) in which Ph and R have the previously-given meaning, and the group of the formula (C,,H is an unbranched alkenylene radical, particularly a l-alkenylene radical, having from three to five carbon atoms and carrying the group R, with a compound of the formula H--Ar, in which Ar has the previously-given meaning, in the presence of a strong Lewis acid, and, if desired, carrying out the optional steps.

The above reaction is carried out according to known methods, for example, by reacting the starting materials in the presence of a strong inorganic acid, e.g. sulfuric acid andthe like. The starting materials used in the above reaction are known or may be prepared according to known methods; particularly useful as starting materials are compounds, in which the group R represents hydrogen;

A resulting salt may be converted into the free base, forexample, by reacting it with an alkaline reagent, such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, metal carbonate, e.g. sodium or potassium carbonate or hydro-gen carbonate and the like; ammonia and the like, or by treatment with a suitable hydroxyl ion exchange resin.

A; resulting; salt, particularly a salt: with an inorganic acid, may be convertedinto another salt, for example, by reacting. it with a suitable metal e.g. sodium, barium,. silver and the like salt-of anv acid, preferably in the presenceof a diluent, in which a resulting ino'rganicsalt is insoluble andis thus removed from the reaction, or treating it with an anion-exchange resin.

A-free base may be converted intoan acid additionsalt thereof by reacting: it or a solution thereof in a suitable solvent or solvent mixture with the acid or a solution thereof, or with a suitable anion exchange preparation, and isolating the desired salt. Asaltmay be obtained-in the form of a hydrate thereof or may include solvent-of crystallization.

An N-oxide of the compounds of 'this invention may be prepared, for example, by treating the free base with a suitable reagent, such as hydrogen peroxide, ozone or a peracid, e.g. peracetic, perbenzoic, monoperphthalic, per sulfuric acid and the like, in a suitable inert solvent. An N-oxide may be converted into a salt thereof according to the above procedure.

The quaternary ammonium derivatives of the compounds of this invention may be obtained, for example, by reacting the base with a reactive" ester of an alcohol and a strong acid, such as, for example, with one of thelower'alkyl ha]ides,.di'- lower alkyl-sulfat'e's,.lowen'alkyl sulfonates; phenyl-lo wer' alkyl halides described above. The quaternizing reactionmay'be performed ini the absence or presence of a solvent, while cooling or at an elevatedztemperaturqdif necessary in a closed vessel and/ or in the atmosphere of aninert gas, e.g; nitrogen and the like: Resulting quaternary ammonium compounds maybeiconverted into other quaternary ammonium compounds; such: as quaternary ammonium hydroxides,- for example, by; reacting a quaternary ammonium halide with silver? oxide; or a; quaternary. ammoniumsulfate with barium. hydroxide,-- by' treating a quaternary ammonium salt with a hydroxyl ion. exchange preparation, by elec trodialysis or any'other suitable method. A" quaternary ammonium hydroxidemay'be converted into a quaternary ammonium salt by reactingthe" former with asuitable acid; A' quaternary. ammonium salt may also'be' con-. verted directly" into another quaternary ammonium salt; for"example, a quaternaryanunonium'iodide may bereacted with freshly preparedsilver chloride or with hydrochloric acid in anhydrousmetlianol to yield the desired quaternary ammonium chloride, or a quaternary ammonium salt may be treated with a suitable anion exchange resin and thus be converted into another quarternary ammonium' salt. A quaternary ammonium compound may be obtained in the form of a hydrate thereof or may contain solvent of crystallization.

A mixture of resulting isomeric compounds may be separated into the single isomers. For example, a mixture of diastereoisomers may be separated into the individual racemic compounds on the basis of physico-chemical differences, such as solubility, for example, by fractional crystallization and the like. Racernates may be resolved into the optically active dand l-forms according to known resolution procedures, for example, by forming a salt of the free racemic base with one of the optically active forms of an acid containing an asymmetric carbon atom. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D-tartaric (l-tartaric) acid and L-tartaric (d-tartaric) acid, as well as the optically active forms of malic, mandelic, 10- camphor sulfonic, quinic acid and the like. From a resulting salt, the free and optically active base may be obtained according to the method described above, and a free and optically active base may be converted into its acid" addition salt, N-oxide, salt of an N-oxide or quaternary ammonium compound according to the procedures described above.

The invention also comprises any modification of the process wherein a compound formed as an intermediate at any stage of the process, is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which leadto final products mentioned in the beginning as preferred embodiments of the invention.

The following examples are intended to illustrates the invention and are not to be construed as being limitations thereon. Temperatures given in degrees centigrade.

Example 1 A solution of 10.0 g. of 1-(4-hydroxy-phenyl)-indane in xylene is added to a hot mixture of 3.5 of a 50' percent mineral oil suspension of sodium hydride in xylene while stirring The mixture is refluxed for three hours, then cooled to room temperature, and treated dropwise with 8.0 g. of 2N,N-diethylaminoethyl chloride. After refluxing for 16 hours and cooling, the reaction mixture is extracted-With concentrated hydrochloric acid; the aqueous phase is made basic with ammonium hydroxide and extracted'with diethyl ether. The organic extract is washed withwater, dried over sodium sulfate and evaporated to dryness. The residue is'distilled to yield'the 1'[4-(2/-N,i diethylaminoethyl)-oxy-phenyl]-indane of the formula:

1 1 Example 2 The sodium salt of 1-(4-hydroxy-phenyl)-indane, prepared from 20.0 g. of 1-(4-hydroxy-phenyl)-inda.ne and 7.0 'g. of a 50 percent mineral oil suspension of. sodium hydride in xylene, is treated with 17.7 -g. of 3-N,N-di methylaminopropyl chloride, The reaction is carried out as described in Example 1; the resulting l-[4-(3-N,N-dimethylarninopropyl)-oxy-phenyl]-indane of the formula:

boils at 168-170/0.4 mm.

Example 3 The 1-[4-(-N,N-dimethylaminoisopropyl)-oxy-phenyl:]-1 1 indane of the formula I OH is prepared by reacting'l0.0 g. of l-(4-hydroxyphenyl)- indane with 3.5 g. of a 50 percent mineral oil suspension of sodium hydride in xylene, and treating the resulting sodium salt of 1-(4-hydroxy-phenyl)-indane with 7.2 g. of N,N-dimethylarnino-isopropyl chloride according to the procedure described in Example 1; the resulting base boils at 170l73/0.2 mm.; yield: 8.75 g.

Example 4 The sodium salt of 1-(4-hydroxy-phenyl)-indane is prepared by reacting 10.0 g. of l-(4-hydroxy-phenyl )-indane with 2.5 g. of a 54 percent suspension of sodium hydride in xylene according to the method describedin Example 1;'the solutionof this salt is reacted with 5.7 g. of 2-N,N-dimethylaminoethyl chloride, and the reaction mixture is Worked up as .shown in Example 1 to yield ,9' g. of 1-[4 (2-N,N-dimethylarninoethyl) oxyphenyl1-indane of the formula which boils at l74 176/ 0.3 mm. Thehydrochloride salt of 1-[42-N,N-dimethylaminoethyl-oxy-phenyl] indane melts at l78-l80 after recrystallization from a mixture of ethanol and diethyl ether.

.121 f Example 5 The 1-{4-[2-(1-piperidino)-ethyl]-oxy-phenyl} indane of the formula CHz-CHE O-GHz-CH B.P.' 199-201/0.=25 ,mm., is prepared by reacting 10.0 g. r

of 1-(4-hydroxy-phenylJ-indane -with2.5 g.- of a 54 percent mineral oil suspension of sodium hydride in Xylene and treating, the resulting salt withi8.7 g., of 2-.( 1-piperi-' dino)-ethy1 :chloride; ,8.5v g. of the desired 1-{4-[2-( 1- piperdino)-ethyl]koxy-phenyH-indaue. is. recovered and converted into its hydrochloride salt, M.P. -163. (after recrystallizationfrom-"a mixture of ethanol-and diethyl ether);

Example. '6

To a mixture of 1.67 grof sodium hydride v(as a 50percent suspension in mineral oil) in 50 m1; of xylene while heating almost to reflux, is added dropwise a'solution of 7 g. of 1-(3-chloro-4-hydroxy-phenyl)-indane in grylene. The reaction mixture is refluxed for three hoursyfa solution of 3.8 g, of 2-N,N diethylamin'oethyl chloride in-xylene is then added while stirring; and refluxing is continued overnight. After cooling, the reaction mixture is 1 acidified .by cautiously adding 15 percent aqueous hydrochloric acid. The aqueous layer: is separated, made basic with ammonium hydroxide and extracted with diethyl ether; The organic phase is separated, washed with water, dried over magnesium sulfatev andevaporated to yield the 1- 3-chloro-4- (2-N,N die thylaminoethyl) -oxyphenyl1-indane of the formula o,.-oH, oH;-N o,11,

;WhiCh isconverted into its hydrochloride, M.P. l47-149f, by treating a solution of the free base in ethanol with hydrogen, chloride .andirecrystallizing thefsalt from ethanol.

. The starting'materia1 used-in the aboveprocedure is; prepared as follows: Atotal'of 42.0 g. of 1-(4-hydroxy-,

phenyl)-indane is& gradually added to a solutionrof 4.6. g. of sodium:in;200 ml.- of ethanol. The reaction mixture organic layer is separated,=dried over magnesiurrisul-fate and evaporated to yield the l (3 chloro-.4-hydroxy,- j Phenylji-inda'ne, which? purified by distillation and is 'col 13 lected at 160-163/0.5 mm. A small amount of the 1(3,5-dichloro-4-hydroxy-phenyl)-indane is collected at 175/ 0.5 mm.

Example 7 A mixture of 2.4 g. of 1-(4-hydroxy-phenyl)-1-methyl- 1,2,3,4-tetrahydro-naphthalene and 0.5 g. of a 53 percent suspension of sodium hydride in 20 ml. of N,N-dimet-hylformamide is stirred for one hour and then treated with 1.16 g. of 2-N,N-diethylaminoethyl chloride in 20 ml. of toluene. The reaction mixture is allowed to stand at room temperature for 18 hours, concentrated to a volume of about ml. and diluted with water. The organic material is extracted with diethyl ether; the organic extracts are combined and washed with 1N aqueous hydrochloric acid. The acid solution is .made basic with concentrated ammonium hydroxide, and the desired 1-[4- (2-N,N-diethylaminoethyl -oxyphenyl] l-methyl1,2,3,4- tetrahydro-naphthalene of the formula o-OE -CH -Nwmm l-CH3 is extracted with diethyl ether, and isolated by evaporating the dried ether solution and distilling the residue, B.-P. 159-161/0.05 mm.

The starting material used in the above procedure is prepared as follows: A mixture of 16.2 g. of l-methyl-l, 2,3,4-tetrahydro-naphthalene, 18.8 g. of phenol and 2.5 g. of aluminum chloride in 200 m1. of hexane is stirred for one hour at room temperature and for another hour at 40-50". After standing overnight at room temperature, the reaction mixture is again warmed to 4050, filtered while warm, and the filtrate is stirred into 200 ml. of warm water. The organic layer is separated, washed with dilute aqueous hydrochloric acid, water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The 1-(4- hydroxy-phenyl)-1-methyl-1,2,3,4 tetrahydro naphthalene, obtained as a slightly brown oil, crystallizes, M.P. 123-124.

Example 8 To a solution of 3.17 g. of 1-[3,-5-dichloro-4-hydroxyphenyl]-1-methyl-1,2,3,4 tetrahydro naphthalene in 25 ml. of N,N-dimethylformamide is added 0.48 g. of a 53 percent suspension of sodium hydride in mineral oil; the mixture is stirred for one hour and then treated with 1.35 g. of 2-N,N-diethylaminoethyl chloride in 20 ml, of toluene. The reaction mixture is allowed to stand at room temperature for 18 hours and is then concentrated to a volume of about 10 ml. and diluted with water. The aqueous mixture is extracted with diethyl ether, the organic phase is separated and Washed with 1 N aqueous hydrochloric acid. The desired 1-[3,5-dichloro-4-(2-N, N-diethylaminoethyl)-oxy-phenyl]-1-methyl-1,2,3 ,4-tetrahydro-naphthalene hydrochloride of the formula crystallizes spontaneously, is collected and recrystallized twice from a mixture of acetone and diethyl ether, MP. 1741,75; yield: 2.35 g.

The starting material used in the above reaction is prepared as follows: A solution of 1-(4-hydroxy-phenyl)- 1-methyl-1,2,3,4-tetrahydro-naphthalenc in 13 g. of sulfuryl chloride is heated to reflux for three hours. The excess of sulfuryl chloride is removed under reduced pressure and the remaining dark oil is dissolved in diethyl ether. The organic solution is washed with 25 ml. of a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The dark viscous oil is distilled to yield the colorless 4-(3, 5 -dichloro-4-hydroxyphenyl -1-m'ethyl-1 ,2,3 ,4-tetrahydronaphthalene, B.P. 143/ 0.05 mm.

Example 9 To a mixture of 1.68 g. of sodium hydride preparation (50 percent suspension of sodium hydride in mineral oil) in xylene is added dropwise a solution of 8.8 g. of 1-(3,5- dichloro-4-hydroxy)-indane in xylene While heating almost to refiux. The reaction mixture is refluxed for three hours and treated dropwise with 4.75 g. of 2-N,N-diethylaminoethyl chloride in xylene while stirring. After refluxing overnight, 15 percent aqueous hydrochloric acid is cautiously added; the aqueous layer is separated and made basic with aqueous ammonia. The organic material is extracted with diethyl ether, the organic solution is washed, dried and evaporated to yield the desired 1-[3, S-dichloro 4 (2-N,N-diethylaminoethyl-oxy-phenyl]-indane of the formula which is purified by distillation, B.P. 197200/0.2 mm. Its hydrochloride, formed by adding ethanolic hydrogen chloride and diethyl ether to the free base, melts at 139- 142 after recrystallization from a mixture of ethanol and diethyl ether.

The starting material used in the above example may be prepared as follows: Chlorine gas is bubbled during 45 minutes through a solution of 15 g. of the sodium salt of 1--(4-hydroxy-phenyl)-indane (prepared as described in Example 1) in 225 ml. of carbon disulfide while stirring and cooling. The inorganic precipitate is filtered off, the filtrate is evaporated under reduced pressure and the residue is diluted with water. The organic material is extracted with diethyl ether; the organic solution is dried over magnesium sulfate and evaporated. The residue is distilled to yield the 1-(3,5-dichloro-4-hydroxyphenyl)-indane, B.P. 163165/0.2 mm.

Other compounds, which may be prepared according to the above-described method are, for example,

1- 3-chloro-4-(2-N,N-diethylamino-2-methyl-ethyl)- oxy-phenyl] ind ane,

1-{3-bromo-4-[2-(4-methyl-1-piperazino)-ethyl]- oxy-phenyl}-indane,

S-chloro- 1- [4- 2-N,N-diethylaminoethyl) -oxy-phenyl] indane,

6-chloro-1-{4-[2- l-pyrrolidino)-ethyl]-oxy-phenyl}- indane,

5-methyl-1-{3-[3-(4-morpholino)-propyl}-oxy-phenyl] indane,

2- [4- 2N,N-diethylaminoethyl -oxy-phenyl] -5-methoxyindane,

These compounds may be converted into their pharmaceutically acceptable acid addition salts, e.g. hydrochlo rides, hydrobromides, maleates and the like, according to the previous procedure. The lower alkyl quaternaryammonium halides, such as the methochlorides, methiodides and the like, of these compounds may beprepared, for example, by reacting the free. compounds with an excess of a lower alkyl halide, e.g. methyl iodide andthe like, if necessary in a closedvessel and/ or at an elevated temperature. The N-oxides, which may be obtained by treatment with a suitable organicpercarboxylic acid, e.g. perbenzoic acid and the like, in an inert solvent, especially ,a halogenated hydrocarbon, maybe converted into their 1' acid addition salt according to the procedure described above.

Example 10 The compounds of. this inventionmay be used in the form of compositions for enteral, parenteral or topical use, which contain the new compounds in admixture with a suitable pharmaceutical organic or inorganic, solid or liquid carrier. For making up the preparation there can be employed carriers which do not react with the 1 new compounds, such aswater, gelatine, lactose, starches, stearic acid, magnesium stearate, sodium lauryl sulfate, talc, vegetable oils, alcohol, benzyl alcohol, cetyl alcohol, petrolatum, gums, propylene glycol, polyalkylenelglycols or any other carrier used for pharmaceutical preparations.

The latter may be in solid form, for example, ascapsules,

tablets, drageesand the like, in liquid form, for example, as solutions, suspensions and the like, or as emulsions,

such as creams, oiutments and the like. If necessary, these preparations may contain auxiliary substances, such as preserving stabilizing, wetting, emulsifying, coloring,

flavoring agents and the like, salts for Varying the osmotic pressure, buffers, etc, and may also contain, in combina- ,tion, other useful substances.

Thus, the compounds of this invention, beinguscful in the treatment of superficial dermatophytoses, may be of a compound having the following formula:

in which Ph, the group -(C H Am, the group I "(C;,,'H' m') Hal 'andthe'lctter p have the previously given meaning, being particularly 1,2-phenyle ue, an unapplied in the; formof pharmaceuticalcompositions for topical use, containing from about 0.1 percent'to-about 10 percent, especially from about 0.5.;percent to about .5 percent, of the active ingredient, particularly 16 8 branched alkylene radical having two carbon atoms, N,N- di-lower alkyl-amino, an alkyleneiradical having two carbon atoms and, separating Am from the oxygen atom by two carbon atoms (i-.e. 1,2-ethylene),'chl0ro, and the integer 1, respectively, or an acid addition, particularly a pharmaceutically acceptable acidaddition, salt thereof. The compositions may be formulated according to known methods used in the art of manufacturing pharmaceutical preparations;

For example, an ointment containing 1 percent of 1-[3- .chloro-4- (2-N,N-diethylaminoethyl)-oxy-phenyl] indane hydrochloride as the activeingredient is prepared as follows-(for 100.0 g.)

Ingredients: G.

1 [3 chloro-4-(2-N,N diethylaminoethyl)=oxyphenyl]-indaue. hydrochloride 1.0 Liquid ,petrolatum 5.0 White petrolatum 94.0

The 1- [3 -chloro-4- 2-N,N diethylami noethyl) oxy-phenyl] -indane hydrochloride is mixed with the liquid petro:

lat-um by using a-mortar untilan adequate reduction in particlesize is accomplished; The white petrolatum is thenslowly blended ,with thismixture; the ointment is passed through a threeroller mill, iuntil total uniformity; 'is obtained and filledinto epoxy lined tubes (5 g.).

A cream, containing 1 percent :of l-[3-chloro-4-(2- N,N diethylaminoethyl)-oxy-phe-nyl] -indane hydrochorid'e as' the active ingredient is prepared as follows (for 100.0-g.):

Ingredients: i G.

1-[3-chloro-4-(2-N,N diethylaminoethyl)I-oxyphenyl]-indane. hydrochloride.-. 1.0 Propylene glycol 15.0. Sodium lauryl sulfate 2.0 Cetyl alcohol 15.0

Phenyl mercuric? acetate 0.002 Purified water, q.s. 100.0 g.

,The phenylrnercurici acetate is dissolved in65 ml. of water at subsequently the ;sodium1lauryl. sulfate is added and the temperature is reduced to .70". The cetyl alcoholis melted at 70 and added .to the aqueous solution while vigorously agitating Stirring is continued while cooling the mixture to 45 phenyl] -indane; hydrochloride is dispersed in the propylene glycol at 45- andadded to the above emulsion while;

agitating. Sufficient water; is added .tobringthe weight to g.,andmixing is continuedwhile the product cools to iroom temperature. The cream is passed through a three,

rollermilliuntil total-uniformity isaccomplished and is filled into epoxy lined tubes (5 g.)

A substituent may be introduced into the ;1,2 -phenylene. portion-eta ;resulting compound; For exampleyupon nitration with a suitable nitrating reagent a nitro group 1 maybe introduced into. the aromatic portion. Substituents attached .to. the: 1,2-phenylene portion ofthe resulting compounds may; be: converted intoiothcr substituents.

For example, a ,nitrogroup may be converted into other substituents. For example,.a nitro' group may be reduced to an amino :group; according ,to vknown reduction meth:

ods, for example, "by controlled treatment with hydrogen inthe presence of a suitable catalyst, e.g. palladium on charcoal andythelike, andof aninert solvent, -e.g. p-

.dioxane and the like, or convertedinto an:N,N-di-lower alkyl amino, particularly N,N-dimethylamino, group, if the reductionis carried out in the presence of a lower alkanal, particularly formaldehyde. An amino group may be converted tinto a'halogeno atom by diazotization, followed by treatment'with a cuprous halide according to the ,Sandmeyer reaction. Or, lower. a'lkoxy, e.g. methoxy and the like, group may be converted into a;free hydroxyl group 'by acidic ;hydroly'sis, for example,"by treatment with hydrobromie acid in the presence of acetic acid and the; like.

The l-[3-chloro-4-(2 N,N Adiethylatninoethyl) oxy-' What is claimed is:

1. A pharmaceutical composition for topical use containing from about 0.1 percent to about 10 percent of a member selected from the group consisting of a compound having the formula H2)n' in which Ph stands for a member selected from the group consisting of 1,2-phenylene, (lower a1kyl)-1,2- phenylene, (lower alkoXy)-1,2-phenylene, (halogeno)- 1,2-phenylene, (nitro)-1,2-phenylene, (N,N-di-lower alkyl amino) 1,2 phenylene and (trifiuoromethyl)-1,2- phenylene, the group of the formula (CH represents unbranched alkylene having from two to three carbon atoms, Am is a member selected from the group consisting of N,N-lower alkyl-amino, N,N-alkylene-irnino, in which alkylene has from four to seven carbon atoms, 4-morpholino and 4-lower alkyl-l-piperazino, the group of the formula (C H represents alkylene having from two to three carbon atoms and separating the group Am from the oxygen atom by two to three carbon atoms, Hal is chloro and the letter p stands for one of the integers 0, 1 and 2, and a pharmaceutically acceptable, non-toxic acid addition salt thereof, the N-oxide thereof, :a pharmaceutically acceptable acid addition salt of the N-oxide thereof and a pharmaceutically acceptable quaternary ammonium salt thereof as the active ingredient, together with a pharmaceutically acceptable carrier therefor.

'2. A pharmaceutical composition for topical use containing from about 0.5 percent to about 5 percent of 1 [3-chl.oro-4-(2-N,N-di-ethyla.minoethyl)-oXy-phenyl] indane, together with a pharmaceutically acceptable carrier therefor.

3. A pharmaceutical composition for topical use containing from about 0.5 percent to about 5 percent of an acid addition salt of 1-[3-chloro-4-(2-N,N-diethylaminoethyl)-oxy-phenyl]-indane, together With a carrier therefor.

References Cited by the Examiner UNITED STATES PATENTS 2,510,946 6/1950 Baker 16758 2,524,738 10/1950 Snell et a1 167-58 2,763,687 9/1956 Kerwin et al 260570.7 2,796,435 6/1957 Goldberg et al. 260570.7

LEWIS GOTTS, Primal Examiner.

CHARLES B. PARKER, FRANK CACCIAPAGLIA,

]R., Examiners.

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Classifications
U.S. Classification514/650, 564/287, 544/59, 548/575, 564/299, 546/205, 540/609, 514/239.2, 568/734, 564/337, 540/450, 544/174, 544/383, 250/396.00R, 564/280, 514/252.12, 544/398, 564/298
International ClassificationC07D295/092
Cooperative ClassificationC07D295/088
European ClassificationC07D295/088